The long-term career goals are to develop the clinical discipline of pharmacogenomies and the short-term goal is to develop an independent patient-oriented research career focusing on the validation and development of pharmacogenentic diagnostics. Environment: The University of Louisville has adopted pharmacogenetics as one of seven key areas for development. The Pharmacogenetic Diagnostics Laboratory (founded by Dr's Valdes and Linder) is one of the first CLIA certified clinical pharmaeogenetic laboratories in the world. Dr C. McClain (Co-mentor) is Director of the newly established Clinical Research Center at the University of Louisville Hospital. Preliminary findings: Within the proximal promoter of the CYP2E1 gene is a nucleotide sequence (cytokine response element) responsible for gamma-interferon (gamma-IFN)-dependent suppression of gene transcription. A naturally occurring polymorphisrn, G(-71)T within this sequence renders the CYP2E1 promoter insensitive to suppression by gamma-IFN. Hypothesis: Intracellular production of reactive-metabolic intermediates is regulated by a negative feedback mechanism sensitive to the structure of the CYP2E1 promoter. Polymorphism within the promoter sequence interrupts this feedback and leads to increased toxicity from reactive intermediate products. Approach: To test this hypothesis, we will; i) Investigate the mechanism of IFN-gamma mediated CYP2E1 suppression in humans, ii) Evaluate the influence of IFN-gamma on the LD 50 of CYP2E 1 substrates which undergo metabolic bioactivation, iii) Characterize the molecular detail of IFN-gamma dependent suppression of CYP2E1, and iv) Evaluate the relationship between the CYP2E1*7B allele and selected human diseases influenced by the catalytic properties ofCYP2E1. Significance: This research will identify a novel mechanism to explain variability in susceptibility to human disease resulting from exposure to medicinal and environmental substrates of CYP2E1. These findings may lead to development of a diagnostic test for identifying susceptible individuals and provide insight into potential therapeutic or preventive approaches.